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BACKGROUND: Many phenotypes in animal breeding are derived from incomplete measures, especially if they are challenging or expensive to measure precisely. Examples include time-dependent traits such as reproductive status, or lifespan. Incomplete measures for these traits result in phenotypes that are subject to left-, interval- and right-censoring, where phenotypes are only known to fall below an upper bound, between a lower and upper bound, or above a lower bound respectively. Here we compare three methods for deriving phenotypes from incomplete data using age at first elevation (> 1 ng/mL) in blood plasma progesterone (AGEP4), which generally coincides with onset of puberty, as an example trait. METHODS: We produced AGEP4 phenotypes from three blood samples collected at about 30-day intervals from approximately 5,000 Holstein-Friesian or Holstein-Friesian × Jersey cross-bred dairy heifers managed in 54 seasonal-calving, pasture-based herds in New Zealand. We used these actual data to simulate 7 different visit scenarios, increasing the extent of censoring by disregarding data from one or two of the three visits. Three methods for deriving phenotypes from these data were explored: 1) ordinal categorical variables which were analysed using categorical threshold analysis; 2) continuous variables, with a penalty of 31 d assigned to right-censored phenotypes; and 3) continuous variables, sampled from within a lower and upper bound using a data augmentation approach. RESULTS: Credibility intervals for heritability estimations overlapped across all methods and visit scenarios, but estimated heritabilities tended to be higher when left censoring was reduced. For sires with at least 5 daughters, the correlations between estimated breeding values (EBVs) from our three-visit scenario and each reduced data scenario varied by method, ranging from 0.65 to 0.95. The estimated breed effects also varied by method, but breed differences were smaller as phenotype censoring increased. CONCLUSION: Our results indicate that using some methods, phenotypes derived from one observation per offspring for a time-dependent trait such as AGEP4 may provide comparable sire rankings to three observations per offspring. This has implications for the design of large-scale phenotyping initiatives where animal breeders aim to estimate variance parameters and estimated breeding values (EBVs) for phenotypes that are challenging to measure or prohibitively expensive.

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The phase 3 trials of the bone anabolic drug teriparatide were prematurely terminated because of a preclinical finding of osteosarcoma in rats treated with high doses of teriparatide for near lifetime. Even so, results from these and subsequent clinical trials showed efficacy and tolerability. Based on the phase 3 results and additional preclinical investigations, Forteo (teriparatide) was approved for use in the United States with an indication for the treatment of osteoporosis in patients at high risk for fracture, a boxed warning regarding potential risk of osteosarcoma, a 2-year lifetime limitation of use, other risk mitigations, and a requirement to assess for risk of osteosarcoma in humans treated with teriparatide. Subsequent investigations included five real-world studies directed at assessing a connection between teriparatide and osteosarcoma risk in humans. The early studies did not identify an increased risk of osteosarcoma but were inadequate to sufficiently characterize risk, given the low incidence of this rare form of bone cancer. Learning from these efforts, two studies were undertaken using claims data to identify large cohorts of patients treated with teriparatide and assess whether these patients were found to have osteosarcoma by linking pharmacy claims data with data from cancer registries. These studies showed no increase in osteosarcoma in patients using teriparatide compared with unexposed groups, as well as to the expected population-based background incidence of the disease. Based on this real-world evidence and the totality of data collected from postmarketing use and other clinical investigations, the label was updated in 2020. The changes included addition of information from large observational studies using real-world evidence, removal of the boxed warning, and a revision of the 2-year lifetime limitation. Thus, observational studies with large sample sizes using real-world data can provide supportive evidence to facilitate regulatory decisions including the elimination of a boxed warning. © 2022 Eli Lilly and Company. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Time-dependent traits are often subject to censorship, where instead of precise phenotypes, only a lower and/or upper bound can be established for some of the individuals. Censorship reduces the precision of phenotypes but can represent compromise between measurement cost and animal ethics considerations. This compromise is particularly relevant for genetic evaluation because phenotyping initiatives often involve thousands of individuals. This research aimed to: 1) demonstrate a data augmentation approach for analysing censored phenotypes, and 2) quantify the implications of phenotype censorship on estimation of heritabilities and predictions of breeding values. First, we simulated uncensored phenotypes, representing fine-scale "age at puberty" for each individual in a population of some 5,000 animals across 50 herds. Analysis of these uncensored phenotypes provided a gold-standard control. We then produced seven "test" phenotypes by superimposing varying degrees of left, interval, and/or right censorship, as if herds were measured on only one, two or three occasions, with a binary measure categorized for animals at each visit (either pre or post pubertal). We demonstrated that our estimates of heritabilities and predictions of breeding values obtained using a data augmentation approach were remarkably robust to phenotype censorship. Our results have important practical implications for measuring time-dependent traits for genetic evaluation. More specifically, we suggest that data collection can be designed with relatively infrequent repeated measures, thereby reducing costs and increasing feasibility across large numbers of animals.

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BACKGROUND: Teriparatide, a recombinant human parathyroid hormone analogue, is associated with increased bone mineral density and a decreased risk of fractures. A dose-dependent increase in the incidence of osteosarcoma was observed in toxicology studies conducted in rats. The primary objective of this study was to estimate the incidence of osteosarcoma over a 10-year period among teriparatide-treated patients versus patients unexposed to teriparatide with osteoporosis and patients in the general population using national pharmacy dispensing data linked with data from participating state cancer registries (SCRs) in the US. METHODS: Patients aged 18 years or older with a dispensed teriparatide prescription formed two different cohorts: Teriparatide-Osteoporosis (Teriparatide-OP) was formed by matching teriparatide patients to unexposed patients with osteoporosis and Teriparatide-General Population (Teriparatide-GP) was formed by matching teriparatide patients to general population patients with a dispensed prescription for a medication other than teriparatide. Matching was performed using select demographics and other variables. Study cohorts were linked to SCR data to ascertain osteosarcoma status. To account for missing outcome data from non-participating SCRs, two analytic approaches were used: the first adjusted the person-time at-risk using a coverage fraction and the second restricted the analyses to patients from states with participating SCRs. RESULTS: There were 18 osteosarcoma cases across four study cohorts: the same three cases in the Teriparatide-OP and Teriparatide-GP cohorts, six cases in the Osteoporosis cohort, and nine cases in the General Population cohort. For the analysis using the coverage fraction the incidence rate ratio (IRR) comparing the Teriparatide-OP and Teriparatide-GP cohorts to the Osteoporosis and General Population cohorts was 1.0 (95% CI: 0.2, 4.5) and 1.3 (95% CI: 0.2, 5.1), respectively. When restricting the analysis to patients from states with participating SCRs, the IRR was 0.6 (95% CI: 0.1, 3.6) and 0.8 (95% CI 0.1, 4.0), respectively. CONCLUSION: The estimates of association between teriparatide and osteosarcoma were imprecise due to the small number of observed osteosarcoma cases. However, the incidence of osteosarcoma observed in each study cohort was within the expected range given background rates for the US general population. The evidence generated by this study, in conjunction with other real-world studies evaluating the risk of osteosarcoma, was used to support changes to the US teriparatide label (including removal of the black box warning regarding potential risk of osteosarcoma) and expand treatment options for patients with osteoporosis.

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A neonatal intensive care unit (NICU) can be an extremely stressful environment for infants receiving complex medical care at a pediatric facility. Music therapy can help address the stressful environment by increasing comfort and relaxation as well as decreasing a patient's physiological response of heart rate and respiratory rate. A randomized controlled trial was completed, examining the effects of 2 guitar accompaniment patterns on infants (an arpeggiated pattern and a bass/chord pattern) in a NICU. There were 180 infants enrolled with mean chronological ages of 7.4 ± 6.1 weeks and postmenstrual ages (gestational age at birth + their chronological age) of 39.8 ± 7.9 weeks. All subject enrollees participated in a 12-minute initial music therapy session. Outcome measures included heart rate, respirations, and comfort responses. The results of the research study demonstrated that the arpeggiated guitar pattern had a lower mean heart rate and respiratory across all 3 data points (pre, during, and post intervention); however, the difference in means between the 2 accompaniment pattern groups was not statistically significant. Using the Neonatal Infant Pain Scale (NIPS) to measure comfort response, the results demonstrated no difference between the 2 group accompaniment patterns. Although the results show no significant differences among accompaniment pattern groups, the researchers describe the clinical significance that supports the use of both accompaniment patterns as suitable interventions for infants in the NICU receiving music therapy intervention.

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The Osteosarcoma Surveillance Study was initiated in the United States in 2003 to monitor for a potential association between the osteoporosis treatment teriparatide and osteosarcoma. Osteosarcoma occurs at a background incidence rate of approximately 2.5 cases per million per year in US adults aged 40 years or older. For this study, incident cases of osteosarcoma diagnosed between January 1, 2003, and December 31, 2016, were identified through participating cancer registries in the United States. Information on prior exposure to medications and possible risk factors was obtained by self-report (or proxy report) in telephone interviews. Exposure information was verified through medical record abstraction for a sample of patients. A standardized incidence ratio was estimated to compare the observed and expected numbers of osteosarcoma patients with a prior history of teriparatide treatment. Interviews were completed for 24% (1173) of patients diagnosed with osteosarcoma between 2003 and 2016; three reports of teriparatide use before diagnosis were identified. Based on the background incidence rate, the expected number of osteosarcoma cases among patients treated with teriparatide was 4.17. Given the three observed cases, the standardized incidence ratio was 0.72 (90% confidence interval [CI], 0.20 to 1.86). Demographic characteristics were similar for interviewed and noninterviewed patients. Agreement was >90% between self-reported and chart-recorded exposure to osteoporosis medications. Mean age of interviewed patients was 61 years; 53% of patients were male, 84% were white, and 5% were Hispanic. The prevalence of suspected risk factors for development of osteosarcoma among the osteosarcoma cohort was 19% for history of radiation and 4% for history of Paget's disease of bone. These findings showed that the incidence of osteosarcoma associated with teriparatide use during the 15-year surveillance period was no different than would be expected based on the background incidence rate of osteosarcoma. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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PURPOSE: During preclinical testing, teriparatide caused a dose-dependent increase in the incidence of osteosarcoma in rats. This study compared the incidence rate of osteosarcoma among patients aged ≥65 years treated with teriparatide vs a matched-comparator cohort. METHODS: This population-based comparative-cohort study matched exposure details for each teriparatide user, identified via Medicare Part D prescription claims, and up to four comparators based on age, sex, zip code, date of claim for filled prescription, and number of unique therapeutic classes dispensed. Outcomes were identified via linkage with participating cancer registries. All US state cancer registries were invited to participate. RESULTS: Overall, 153 316 patients in the teriparatide cohort and 613 247 in the comparator cohort were linked to 811 osteosarcoma cases from 26 participating state cancer registries (68% of US patients aged ≥65 years diagnosed 2007-2014). Analysis on a subset of cohorts revealed they were balanced for known osteosarcoma risk factors and Charlson comorbidity index. Mean duration of teriparatide treatment was 10 months. No osteosarcoma cases were observed in the teriparatide cohort; the incidence rate in the comparator cohort was consistent with the background incidence rate among adults aged ≥65 years. The incidence rate ratio was 0.0 (95% confidence interval, 0.0-3.2). CONCLUSIONS: For US patients aged ≥65 years, incidence of osteosarcoma among those treated with teriparatide ranges from 0 to 3.2 times the incidence of osteosarcoma in those treated with other medications. Given low incidence of osteosarcoma, this range of effect is inconsistent with a large absolute increase in osteosarcoma risk.

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There have been very few theoretical models published to understand the relationship between workplace bullying and different outcome variables. Applying the Job Demands Control (JDC) model, this study analyzed workplace bullying alongside 'traditional' job stressors of role overload and low job control to determine the relative associations of each with mental health and wellbeing. These relative associations have not been well documented. Data were obtained from an organizational climate questionnaire administered to 21 Australian Defence Force units (n = 3193). Results indicated that the correlations between bullying and psychological distress (r = 0.39), job satisfaction (r = -0.28), and affective commitment (r = -0.22) were all significant and for some outcomes greater than those involving the traditional job stressors. Furthermore, for each of these three outcomes, bullying contributed incremental variance after controlling for other job demands. These results support earlier claims that workplace bullying requires the same attention given to traditional work stressors. The JDC model provides a strong theoretical base to investigate workplace bullying. Testing against other stressors allows for consideration of the broader context of workplace bullying when managing the workforce.

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This study is the first to examine the diagnostic accuracy of two depression screening scales-the Kessler Psychological Distress Scale (K10) and the Patient Health Questionnaire (PHQ)-in an entire regular-serving military population. Currently serving Australian Defence Force personnel (n = 24,481) completed the K10 and PHQ9. Then a targeted subsample (i.e., the analysis sample, n = 1,730) completed a diagnostic interview to identify DSM-IV 30-day disorder. Weighted results represented the entire population (N = 50,049). Both scales similarly showed a good ability to discriminate between personnel with and without depressive disorders. Optimal cutoffs (19 for K10, 6 for PHQ9) showed high sensitivity and good specificity, and were similar to though slightly lower than those recommended in civilian populations. Both scales appear to be valid screens for depressive disorder in the military, using the cutoffs identified. As both performed similarly, scale choice may depend on other factors (e.g., availability of norms).

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OBJECTIVE: Atomoxetine is a non-stimulant drug indicated for the treatment of attention-deficit/hyperactivity disorder in children aged ≥6 years, adolescents, and adults. In this retrospective cohort study, the incidence and risk of dystonia in children and adolescents treated with atomoxetine was compared to a propensity score-matched cohort of stimulant users. METHODS: Data between 1 January 2006 and 31 December 2014 from patients aged 6-17 years in the Truven Health Analytics MarketScan database were used to generate two cohorts of patients: (1) atomoxetine users and (2) stimulant (methylphenidates or amphetamines) users. A Cox proportional hazards regression model was used to compare incidence of dystonia across propensity score-matched cohorts. RESULTS: Of the 70,657 atomoxetine users, 70,655 users were propensity score-matched to a stimulant user. In the atomoxetine- and stimulant-treated cohorts, the crude incidence rates of dystonia were 54.9 (95% CI: 27.1-82.7) and 77.9 (95% CI: 49.1-106.8) per 100,000 person-years, respectively. The hazard ratio for occurrence of dystonia with atomoxetine use relative to stimulant use was 0.68 (95% CI: 0.36 - 1.28; P = 0.23). CONCLUSION: In this large retrospective cohort study, there was no significant difference in incidence or risk of dystonia among patients treated with atomoxetine compared to stimulants.

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INTRODUCTION: Mental health screens are designed to detect individuals at risk of psychological disorders. In the military setting of this study, these disorders were post-traumatic stress disorder (PTSD) and alcohol use. This study extends the literature on deployment-related mental health screening by including measures of sleep difficulties and anger as predictors of postdeployment PTSD and alcohol abuse. Evidence that measures of anger and sleep difficulties contribute incremental validity to the prediction of postdeployment mental health problems, including substance abuse, would be helpful in designing interventions to assist the rehabilitation of returning personnel. MATERIALS AND METHODS: A test battery containing the PTSD Checklist-Civilian (PCL-C) to screen for PTSD, the Kessler 10 to screen for psychological distress, a Sleep Difficulties scale, an exposure to trauma scale, and an anger scale was administered to 212 personnel nearing completion of a deployment to the Middle East. A second battery containing the PCL-C, the Kessler 10, and a measure of alcohol consumption (Alcohol Use Disorders Identification Test [AUDIT]) was administered to the same personnel 3 to 6 months after return to Australia. Hierarchical regression analyses assessed the predictive validity of measures of psychological distress (anxiety and depression), PTSD symptomatology, sleep disturbance, and anger in relation to postdeployment measures of PTSD symptomatology and alcohol use. RESULTS: Time 1 measures predicted 24.4% of the variance in postdeployment PCL-C scores and 13.1% of the variance in AUDIT scores, with the Sleep Difficulties scale contributing to the prediction of the PCL-C score and the anger scale helping to predict AUDIT scores. CONCLUSION: On the basis of these findings, we recommend the inclusion of improved measures of both anger and sleep difficulties in end-of-deployment mental health screens. A less behaviorally specific and more wide-ranging anger scale is recommended for future studies that aim to evaluate the role of anger in screening batteries. Our findings suggest that the Sleep Difficulties scale used in this study would be a worthwhile addition to mental health screening because it is moderately correlated with both Time 1 and Time 2 measures of PTSD symptomatology and psychological distress. Furthermore, there is minimal stigma associated with the experience of sleep difficulties.

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Depression, alcohol use disorders and post-traumatic stress disorder (PTSD) are serious issues among military personnel due to their impact on operational capability and individual well-being. Several military forces screen for these disorders using scales including the Kessler Psychological Distress Scale (K10), Alcohol Use Disorders Identification Test (AUDIT), and Post-traumatic Stress Disorder Checklist (PCL). However, it is unknown whether established cutoffs apply to military populations. This study is the first to test the diagnostic accuracy of these three scales in a population-based military cohort. A large sample of currently-serving Australian Defence Force (ADF) Navy, Army and Air Force personnel (n = 24,481) completed the K10, AUDIT and PCL-C (civilian version). Then, a stratified sub-sample (n = 1798) completed a structured diagnostic interview detecting 30-day disorder. Data were weighted to represent the ADF population (n = 50,049). Receiver operating characteristic (ROC) analyses suggested all three scales had acceptable sensitivity and specificity, with areas under the curve from 0.75 to 0.93. AUDIT and K10 screening cutoffs closely paralleled established cutoffs, whereas the PCL-C screening cutoff resembled that recommended for US military personnel. These self-report scales represent a cost-effective and clinically-useful means of screening personnel for disorder. Military populations may need lower cutoffs than civilians to screen for PTSD.

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Psychological screening of large numbers of personnel returning from deployments should be as brief as possible without sacrificing the ability to detect individuals who are experiencing serious psychological difficulties. This study focused on screening for posttraumatic stress disorder (PTSD) symptomatology in 421 deployed male members of the Australian Army while they were on deployment and again 3 to 6 months after they returned home. The first aim was to evaluate the performance of the Primary Care--Posttraumatic Stress Disorder Screen (PC-PTSD) and a 4-item version of the 17-item Posttraumatic Stress Disorder Checklist (PCL). A second aim was to evaluate the role of the Kessler-10 (K10) in psychological screening. The results indicated that the short form of the PCL was a better substitute for the full PCL than the PC-PTSD. Other results suggested that a more efficient screening process can be achieved using an initial K10 screening followed by more intensive PTSD screening for people identified as high risk. An additional advantage of an initial K10 filter is that other forms of mental illness could also be targeted in the second-stage screening.

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OBJECTIVES: Military organizations are keen to address barriers to mental health care yet stigma and barriers to care remain little understood, especially potential cultural differences between Armed Forces. The aim of this study was to compare data collected by the US, UK, Australian, New Zealand and Canadian militaries using Hoge et al.'s perceived stigma and barriers to care measure (Combat duty in Iraq and Afghanistan, mental health problems and barriers to care. New Engl J Med 2004;351:13-22). DESIGN: Each member country identified data sources that had enquired about Hoge et al.'s perceived stigma and perceived barriers to care items in the re-deployment or immediate post-deployment period. Five relevant statements were included in the study. SETTING: US, UK Australian, New Zealand and Canadian Armed Forces. RESULTS: Concerns about stigma and barriers to care tended to be more prominent among personnel who met criteria for a mental health problem. The pattern of reported stigma and barriers to care was similar across the Armed Forces of all five nations. CONCLUSIONS: Barriers to care continue to be a major issue for service personnel within Western military forces. Although there are policy, procedural and cultural differences between Armed Forces, the nations studied appear to share some similarities in terms of perceived stigma and barriers to psychological care. Further research to understand patterns of reporting and subgroup differences is required.

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